Activation of the LMP-1 Protein of Epstein-Barr Virus

Epstein-Barr 病毒 LMP-1 蛋白的激活

• 批准号: 6880020
• 负责人: JENNIFER M MARTIN
• 金额: $ 24.42万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880020
• 关键词: B lymphocyte; Epstein Barr virus; biological signal transduction; cell growth regulation; cryoelectron microscopy; latent virus infection; membrane proteins; protein protein interaction; protein sequence; protein structure function; stoichiometry; tissue /cell culture; viral carcinogenesis; virus infection mechanism; virus protein; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human pathogen associated with a variety of cancers, including B cell lymphomas and nasopharyngeal carcinoma. EBV encodes an oncoprotein called the latent membrane protein-1 (LMP-1) whose activity is critical for B cell transformation by EBV. The ultimate goal of the proposed research is to explore the molecular and biochemical mechanisms by which LMP-1 contributes to EBV's life cycle in vitro and then to apply results to LMP-1's potential contribution to EBV's life cycle in vivo as it relates not only to the process of tumorigenesis but to the activity of EBV in latently infected B cells of healthy individuals. LMP-1 is expressed in infected primary B cells, immortalized lypmphoblastoid cell lines, and in some tumor cell lines or biopsies. LMP-1 functions as a constitutively-active cell surface receptor and activates positive growth-regulatory signals via its intracellular C-terminal signaling domain and negative growth-regulatory signals via its transmembrane domain. The studies described in this proposal are designed with the combined goals of understanding the function of LMP-1's hydrophobic transmembrane domain in the context of a) the mechanism of LMP-1's constitutive activation of cellular growth-regulatory signaling and b) signaling resulting in negative growth-regulation. Defining the mechanism of LMP-1's constitutive activation will provide insights into the control of cellular signal transduction and may be generally applicable to the molecular mechanisms involved in normal B cell growth control and in the aberrant growth of virally and nonvirally induced malignancies. Understanding the process of negative growth-regulation by LMP-1 will provide insights into the broad areas of cell cycle regulation and cytokinesis, and may shed light on the contribution of LMP-1 to EBV's life cycle in vivo, in transformed cells and in latently infected cells in healthy seropositive individuals.

描述（由申请人提供）：EB病毒（EBV）是一种与多种癌症相关的人类病原体，包括B细胞淋巴瘤和鼻咽癌。EBV编码一种称为潜伏膜蛋白-1（LMP-1）的癌蛋白，其活性对于EBV转化B细胞至关重要。该研究的最终目标是探索LMP-1对EBV体外生命周期的分子和生化机制，然后将结果应用于LMP-1对EBV体内生命周期的潜在贡献，因为它不仅与肿瘤发生过程有关，而且与健康个体潜伏感染的B细胞中EBV的活性有关。LMP-1在感染的原代B细胞、永生化的淋巴母细胞样细胞系和一些肿瘤细胞系或活检组织中表达。LMP-1作为组成型活性细胞表面受体发挥作用，并通过其细胞内C-末端信号传导结构域激活正生长调节信号，并通过其跨膜结构域激活负生长调节信号。本提案中描述的研究设计的组合目标是理解LMP-1的疏水跨膜结构域在a）LMP-1的细胞生长调节信号传导的组成性激活机制和B）导致负生长调节的信号传导的背景下的功能。定义LMP-1的组成性激活机制将提供对细胞信号转导控制的了解，并且通常可适用于正常B细胞生长控制以及病毒和非病毒诱导的恶性肿瘤的异常生长中所涉及的分子机制。了解LMP-1的负生长调节过程将为细胞周期调节和胞质分裂的广泛领域提供见解，并可能揭示LMP-1对EBV体内、转化细胞和健康血清阳性个体中潜伏感染细胞的生命周期的贡献。